Mechanical, Thermal and Transport Properties of Mutated Hemoglobin Protein of Sickle Cell

Abstract

The Asia, Africa and states of the northern hemisphere are continuously suffering from sickle cell disease. Many of the physical factors have been studied interestingly for sickling of hemoglobin protein in the blood of sickle cell anemia patients. In the present work, we carry on a systematic study of sickle and non-sickle hemoglobin proteins to understand their structural, thermodynamics and transport properties at 310 K using the molecular dynamics (MD) technique. We have used the TIP3P water model as a solvent and all-atom charmm36m modified force field parameters to model our system. We have estimated the root mean square deviation (RMSD), number of hydrogen bonds, salt bridges, hydrophobic, van der Waals (vdW) and electrostatic interactions and solvent accessible surface area (SASA) of sickle and normal hemoglobin proteins to investigate the structural conformation. We observed a higher number of hydrogen bonds, salt bridges, and hydrophobic interactions in sickle hemoglobin protein than that of normal. Also, sickle protein has shown a large value of vdW and electrostatics interactions in comparison to normal Hb protein tetramer. Our investigation shows that the SASA of normal hemoglobin is much less than that of sickle hemoglobin as expected in both tetramer and dimer, which may be due to the sickle shape of hemoglobin. The reduction in the contact area of the alpha chain indicates less bonding energy in the alpha chain with the other three chains in sickle hemoglobin protein than in the alpha of normal hemoglobin protein. This means sickle hemoglobin is more hydrophilic than normal hemoglobin. This finding indicates stronger confinement in sickle hemoglobin protein. This work has further extended on identifying the binding components to realize the stiffness and their folding pathways in the sickle and normal hemoglobin proteins to explore the elastic properties using steered molecular dynamics (SMD). This study of beta and alpha chains in the hemoglobin proteins assures that a higher amount of force is required to separate the alpha and beta chain of normal hemoglobin than that of sickle hemoglobin. It also implies that the beta chain contributes more stiffness to the hemoglobin protein. The force for breaking the bonding in alpha chain in normal protein is higher than in sickle indicating that the alpha chain has higher stiffness in normal than in sickle hemoglobin protein. Both studies indicate higher stiffness in sickle hemoglobin is due to the contribution of the beta chain. It supports the theoretical concept of higher free energy in normal than in sickle hemoglobin protein. Moreover, the specific heat capacity of normal hemoglobin and sickle hemoglobin proteins have been estimated. The normal hemoglobin protein has a higher specific heat capacity than that of the sickle hemoglobin protein. Also, the self and binary diffusion v coefficients of sickle is obtained less than that of normal hemoglobin protein dimer. The diffusion coefficient of sickle and normal hemoglobin are also increased with temperature in usual way. We have also estimated the binding free energy of dimerization. The binding free energy of alpha and beta chains in the hemoglobin protein dimer structure of sickle and normal is found to be (5.97±0.27) kcal/mol and (6.64±0.27) kcal/mol. The difference in free energy in the sickle and the normal hemoglobin is estimated as (0.67±0.06) kcal/mol. Thus, it is recommended to increase the free energy carried by sickle protein to work as normal protein.